Manufacture of bipyridylium salts

ABSTRACT

A process for the manufacture of a 1,1&#39;&#39;-disubstituted-4,4&#39;&#39;bipyridylium salt which comprises treating the corresponding 1,1&#39;&#39;-disubstituted-1,1&#39;&#39;,4,4&#39;&#39;-tetrahydro-4,4&#39;&#39;-bipyridyl with an organic compound which has a redox potential in water more positive than -1.48 volts as compared with the saturated calomel electrode and which reacts with a hydride ion with the formation of an anion which under the conditions of the reaction has a redox potential more positive than -0.45 volt as compared with the saturated calomel electrode.

ilnited States Patent [w] Colchester et al.

n 3,714,174 [45} Jan. 30, 1973 [54] MANUFACTURE OF BIPYRIDYLIUM SALTS[75] inventors; John Edward Colche s ter; John Gerard Carey, both ofRuncorn, England [73] Assignee: I h ipeFial Chemical fid iis ti' iesLimited,- London, England [22] Filed: Dec. 5, 1969 21 Appl. No.: 882,699

[30] Foreign Application Priority Data Dec. 20, 1968 Great Britain..60,7l 3/68 [52] US. Cl ..260/295 AM, 260/296 D, 71/94 [5 1] Int. Cl...C07d 31/44 [58] Field of Search .260/295 AM, 296 D l 56] ReferencesCited UNlTED STATES PATENTS 3,405,135 10/1968 Colchester et a]. ..260/295 AM Primary ExaminerAlan L. Rotman AuorneyCushman, Darby & CushmanABSTRACT A process for the manufacture of a 1,1 '-disubstituted-4,4-bipyridylium salt which comprises treating the corresponding l,l'-dis'u'bstituted-l ,l ,4,4-tetrahydro- 4,4'-bipyridy| with an organiccompound which has a redox potential in water more positive than l.48volts as compared with the saturated calomel electrode and which reactswith a hydride ion with the formation of an anion which under theconditions of the reaction has a redox potential more positive than 0.45volt as compared with the saturated calomel electrode.

10 Claims, No Drawings MANUFACTURE OF BIPYRIDYLIUM SALTS This inventionrelates to the manufacture of bipyridylium salts and particularly to aprocess for the manufacture of l,1disubstituted-4,4-bipyridylium saltswhich are useful herbicides by oxidation of the corresponding l,l'-disubstituted-l ,l ',4,4'-tetrahydro- 4,4'-bipyridyl.

In U.K. Patent Specification No. l,073,08l we have described and claimeda process for the production of an N,N'-(orl,l'-)-disubstituted-4,4'-bipyridylium salt by treating an N,N-(orl,l-)-disubstituted tetrahydrobipyridyl with an oxidizing agent that isan organic compound which is a hydrogen acceptor and which has a redoxpotential in an aqueous system more positive than l.48 volts withrespect to the saturated calomel electrode.

We have now found that particularly suitable oxidizing agents forforming the bipyridylium salt are organic compounds which oxidize thetetrahydrobipyridyl and which react with a hydride ion [H with theformation of a stable anion; such anions have a redox potential underthe conditions of the reaction more positive than 0.45 volts withrespect to the saturated calomel electrode.

Oxidation of the tetrahydrobipyridyl is believed to occur initially byremoval of the hydride ion [H therefrom to form an intermediateoxidation product, the hydride ion being accepted by the oxidizing agentto form an anion. The intermediate oxidation product is believed toreact immediately with a further molecule of the oxidizing agent withremoval of a hydride ion from the intermediate and formation of a secondanion. The overall reaction is therefore oxidation of thetetrahydrobipyridyl to the correspondingl,l-disubstituted-4,4'-bipyridylium di-cation with formation of twoanions. In order that the oxidation may proceed as above the anionformed in the initial stage of the oxidation must not abstract a protonfrom the intermediate oxidation product, and anions having this propertyare defined for the purposes of this specification as stable anions;they have redox potentials more positive than 0.45 volt. An alternativedefinition of the stable anion is that it is an anion which isstabilized by the l,l 'disubstituted-4,4'-bipyridylium di-cation (thefinal oxidation product of the tetrahydrobipyridyl) under the conditionsof the reaction.

According to the present invention we provide a process for themanufacture of a l,l '-disubstituted-4,4 '-bipyridylium .salt whichcomprises treating the corresponding l,l '-disubstituted-l ,l,4,4'-tetrahydro-4,4 -bipyridyl with an organic compound which has aredox potential in water more positive than -l .48 volts as comparedwith the saturated calomel electrode and which reacts with a hydride ionwith the formation of an anion which under the conditions of thereaction has a redox potential more positive than 0.45 volt as comparedwith the saturated calomel electrode.

The reaction may be carried out conveniently in solution, usually in asolvent which will dissolve the N,N'-disubstituted tetrahydrobipyridyland preferably also the oxidizing agent. Suitable solvents includeethers, for example diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, bis-(Z-methoxyethyl) ether, and 1,4- dioxane; ketones,for example acetone; nitro compounds, for example nitroalkanes;nitriles; hydrocarbons, for example benzene and hexane; organic bases,

for example pyridine; halogenated hydrocarbons, particularly chlorinatedhydrocarbons, for example chlorobenzene, chloroform andtrichloroethylene; amides, particularly tertiary alkylamides for exampledimethyl formamide; sulphoxides, for example dimethyl sulphoxide;sulphones for example sulfolane; and propylene carbonate. Although theiruse tends to lead to somewhat lower yields of bis-quatemary salts thancan be obtained with the above-mentioned solvents, the reaction may alsobe carried out in other solvents if desired, for example in alcohols(including glycols) for example ethylene glycol, diethylene glycol,methanol, 2-(2-methoxy ethoxy) ethanol, and isopropanol. Mixtures ofsuch solvents may be used if desired.

The N,N'-disubstituted tetrahydro-4,4'-bipyridyl may be in particular anN,N'-dialkyl tetrahydro-4,4'- bipyridyl, in which case our selectedoxidizing agents are especially useful in giving good yields which arenot obtainable with other oxidizing agents. The N,N'-dialkyltetrahydrobipyridyl may be made in known manner for example by reducingan aqueous solution of an N- alkyl pyridinium salt (for example N-methylpyridinium iodide) with sodium amalgam or by electrolytic reduction.Alternatively it may be made by treatment of the sodium derivative oftetrahydrobipyridyl with an alkyl halide. The process may also beapplied to tetrahydro- 4,4'-bipyridyls having a variety of otherN-substituents, for example benzyl groups. In the case of l,l '-dialkyltetrahydrobipyridyls the alkyl groups advantageously contain from one tosix carbon atoms.

There may also be used, in particular, those tetrahydrobipyridyls havingas N-substituents a carbamidoalkyl group, especially anN,N-disubstituted carbamidomethyl group. Such compounds may be obtainedby electrolytic reduction of the corresponding Nsubstituted pyridiniumsalt, as is more fully described in U.K. Patent Specification No.1,073,082. The bipyridylium salts produced from these compounds may bemade alternatively by reacting an N,N-disubstituted amide of ahalogenated aliphatic monocarboxylic acid (especially anN,N-disubstituted chloroacetamide) with 4,4-bipyridyl. Thecarbamidoalkyl groups are of the structure R,--CO-NR R in which R, is ahydrocarbon radical (usually a methylene group CH and R and R arehydrocarbon or substituted hydrocarbon radicals especially alkyl groupscontaining from one to four carbon atoms; the group R and R may,together with the attached nitrogen atom, form a heterocyclic ring (forexample a piperidine or morpholine ring) which may optionally besubstituted.

In the tetrahydrobipyridyls the'pyridyl nuclei may be substituted in the2, 3, 5 or -positions.

The reaction may be carried out conveniently at ambient temperatures,though higher or lower temperatures may also be used if desired forexample from 0C to 200C, preferably not greater than C. The particularreaction conditions to be employed in any particular instance will, ofcourse, depend to some extent upon the particular reactants and solventemployed and can be determined by simple experiment.

The concentration of the tetrahydrobipyridyl is not critical and we havefound that a concentration of about 0.5 mole per liter is satisfactory.For optimum results the amount of the oxidizing agent should be suchthat the molar ratio of the oxidizing agent to the tetrahydrobipyridylis at least 2:1 and an excess of the oxidizing agent will normally beemployed. Conveniently of the oxidizing agent can be employed as asolution in which case the concentration of the agent can be suitablyabout 0.5 mole per liter. A particularly suitable technique is to add asolution of the oxidizing agent of concentration about 0.5 mole perliter to a solution of the tetrahydrobipyridyl also of concentrationabout 0.5 mole per liter.

The organic oxidizing agent reacts with a hydride ion with the formationof a stable anion. There are two ways in which this anion can be formedand in each case an addition reaction takes place between the organiccompound and the hydride ion. This addition product may itself be thestable anion, or the addition reaction may be accompanied by asimultaneous displacement reaction wherein an atom or a group isdisplaced from the organic compound in the form of the stable anion. Theaddition of the hydride ion and the displacement of the atom or group inthe form of the stable anion occur at different sites in the molecule ofthe organic compound.

Among those organic compounds which undergo an addition reaction withthe hydride ion to form. an interaction product which is itself a stableanion there may be mentioned in particular cyclic organic compoundswhich on addition of the hydride ion give rise to anions having ahighlyconjugated ring structure and having one or more atoms of highelectronegativity able to sustain a negative charge. Theelectronegativity of the atom or atoms able to sustain a negative chargeshould be greater than 2.5 on the Pauling Scale. The anions derived fromthese compounds have aromatic character and possess the characteristicclosed system of 1r electrons as do all atomatic anions. For conveniencesuch anions are hereinafter called aromatic anions.

As cyclic organic compounds which may be used there may be mentioned inparticular cyclic com-,

vpounds containing either two heterocyclic nitrogen atoms oralternatively a heterocyclic nitrogen atom and a heterocyclic carbonatom of a carbonyl group. Examples of compounds of this class areisatin, flavin and its derivatives, for example riboflavin, alloxan,isoallox azine, alloxazine, indophenols, indigo and its derivatives,pyrazolinones, 'oxindolones; imidazolinones and indazolinones.

Examplesof other cyclic compounds which result in the formation of .astable aromatic anion directly are those containing two'or more carbonylgroups in the cyclic structure, for example indane trione.

A further class of organic compounds which react with a hydride ion toform a stable anion directly is that class of compoundswhich contain oneor more atoms of high electronegativity anda mesomeric potentialsufficient to sustain a negative charge. An example of such a compoundis tetracyanoethylene.

Asstated hereinbefore a second general class of organic compounds whichmay be used are those which react with a hydride ion and from which astable anion is displaced as a result of the reaction. These compoundsmay containan anion which is displaced as a stable anion oralternatively they may contain an atom or group which is capable ofbeing displaced as a stable anion. Examples of the former type ofcompound are nitrogen quaternary salts of suitable redox potential, forexample pyridinium and phenazinium salts; and other salts such aspyrillium salts, thiapyril salts, sulphonium salts, for examplemethylene blue, and N- benzylnicotinamide quaternary salts.

After interaction of the N,N'-disubstituted-4,4- tetrahydrobipyridyl andthe oxidizing agent, there is formed a product which appears to be anaddition product and is highly colored. This material reacts as a1,1'-disubstituted-4,4'-bipyridylium salt and the organic anion may bereleased from it by treatment with a mineral acid, particularlyhydrochloric acid, sulphuric acid, phosphoric acid, or acetic acid,though other acids may be used if desired.

For this acid treatment, temperature is not a very critical factor and avariety of temperatures may be used. The acid treatment produces thebipyridylium salt and the reduced form of the oxidizing agent. Thebipyridylium salt and the by-products of reduction of the oxidizingagent can be recovered by conventional means.

The process of our invention has the advantages of providing very usefulyields of bis-quaternary salts, as high as 80 percent or more of theory.It also has the advantage that it enables different salts to be preparedat will by use of the appropriate acid in the final stage; this providesa simple route to salts which-are less corrosive than the chlorideswhich are usually the most accessible ones by the processes formerlyavailable.

The invention is illustrated but in no way limited by the followingexamples.

Examples 1-9 ture was stirred for 3 hours after the final addition ofthe tetrahydrobipyridyl solution and the resulting solid precipitate wasthen filtered off. ZN-hydrochloric acid (50 ml) was then added todecompose the reduced alloxan and to yieldN,N'-dimethyl-4,4'-bipyridylium dichloride. The resulting precipitatederived from the reduced alloxan was filtered off; the filtratecontained TABLE Reaction Ex. Time No. Oxidizing agent Solvent (hrs.)Efficiency l 1 Alloxln monohydrate Toluene 3 2 Riboflavin DMF 3 36.5 3p-quinone dioxime Diglyme 2 20 4 Benzal barbituric acid Diglyme 35 5Indigo 4.5 20

6 lsatin Methyl 4 45 cyanide 7 lndane trione Ethyl 4 65 acetate 8 Methylred DMF 4 45 9 Methyl violet DMF 4 40 Reaction efficiencies are based onN,N'-dimethyl tetrahydro-4,4- bipyridyl fed. DMF representsdimethylformamide.

Examples 10-13 A solution of N,N'-dimethyl tetrahydro-4,4- bipyridyl(0.156 mole) in toluene (50 ml) was added under an atmosphere ofnitrogen to a solution of N- benzyl-3carboxamidopyridinium chloride(0.04 mole) in anhydrous ethanol (100 ml) at 25C. The mixture wasstirred for hours after which time toluene (100 ml) and then water (100ml) were added. The aqueous phase was separated from the organic phaseand was found to contain 1.93 gm of N,N'-dimethyl-4,4'- bipyridyliumdichloride (50% efficiency) by spectrophotometric analysis.

This procedure was repeated three times (Examples 1 I, 12 and 13) butusing the solutions of the oxidizing agents in the solvents shown inTable 2 below.

TABLE 2 Reaction* Ex. Oxidizing Agent Solvent Time Efficiency No. (hrs.)(70) 10 N-benzyl-3-carbamido- Toluene 20 50 pyridinium chloride 1 lMalachite green DMF 2 12 Methylene blue DMA 3 80 I3 Triphenyl-2,4,6-Methyl pyrylium chloroferrate cyanide/ 4 40 acetone based ontetrahydrobipyridyl fed. DMA represents dimethylacetamide.

Examples 14-38 The experimental procedure in each example was as followsA solution of l,1-dimethyl-1,l',4,4'-tetrahydro-4,4 -bipyridyl (0.0156mole) in toluene (50 ml) was added dropwise over a period of 1 hour to astirred solution of the oxidizing agent (0.04 mole) in the specifiedsolvent at room temperature under an atmosphere of nitrogen. Theresulting mixture was then maintained at the specified temperature forthe stated period, after which time an excess of dilute hydrochloricacid was added. The resulting mixture was analyzed and was found tocontain 1,1 '-dimethy1-4,4bipyridylium cation in each example.

The results are shown in Table 3, in which reaction efficiencies arebased upon tetrahydrobipyridyl fed:

19 Indigo DMF 25 4 16 20 lsatin CH CN 25 4 57 21 p-quinone dioxime CH,CN25 4 36 22 p-quinone dioxime Diglyme 25 2 20 23 N-mcthylmaleimideDiglyme 25 2 33.5

(100) 24 Phthalamide CH CN 25 4 5.8

25 Phenolphthalcin CH CN 25 3 6 (75) 26 DMF 25 2 32 27 Malachite greenCH CN 2S 4 32 0) 28 Methyl red CH CN 25 4 30 (200) 29 Methyl red DMF 254 44 30 Methyl violet CH CN 25 4 53 31 Methylviolet DMF 25 4 35 32Methylene blue DMA 25 3 33N-methyl phenazonium CH CN 25 4 63methosulphate (200) 34 2,6-diphenylpyrylium CH CN 20 4 15 FeCl. (200) 352,4,6-triphenyl CH CN 20 4 35 pyrylium FeCl; (200) 36N-benzylnicotinarnidc Ethanol 20 20 50 chloride 100) 37 m-dinitrobenzeneToluene 80 4 l0 Toluene() 38 Beta-nitrostyrcne Toluene 5 I0 What weclaim is:

1. A process for the manufacture of a 1,1 lower alkyl or carbamido loweralkyl-disubstituted -4,4-bipyridy lium salt which comprises treating at20C to 80C the corresponding 1 ,1 -disubstituted-1 ,1 '-4,4'-tetrahydro-4,4'-bipyridyl with an organic oxidizing agent which has a redoxpotential in water more positive than -1.48 volts as compared with thesaturated calomel electrode and which reacts with a hydride ion removedfrom the said tetrahydrobipyridyl to form a stable anion which under theconditions of the reaction has a redox potential more positive than 0.45volt as compared with the saturated calomel electrode, said oxidizingagent being selected from the group consisting essentially of alloxan,alloxan monohydrate, riboflavin, p-quinone dioxime, benzal barbituricacid, isatin, indane trione, methyl red, methyl violet,N-benzyl-3-carbamidopyridinium chloride, malachite green, methyleneblue, triphenyl-2,4,6,-pyrylium chloroferrate, N-methyl maleimide,phthalimide, phenolphthalein, M-methyl phenazonium methosulphate,2,6-diphenyl pyrylium chloroferrate, N-benzyl nicotinamide chloride,mdinitrobenzenc and beta-nitrostyrene, the said oxidizing agent andbipyridyl being dissolved in an inert organic solvent therefor.

2. A process as claimed in claim 1 wherein the temperature is less thanC.

3. A process as claimed in claim 1 wherein the tetrahydrobipyridyl isemployed in the form of a solution in which its concentration is about0.5 mole per liter.

4. A process as claimed in claim 1 wherein the organic oxidizing agentis employed in the form of a solution in which its concentration isabout 0.5 mole per liter.

substitutents of the tetrahydrobipyridyl are carbamido lower alkylgroups.

9. A process as claimed in claim 1 wherein the said carbamidoalkylgroups are N,N-dialkyl carbamidomethyl groups.

10. A process as claimed in claim 1 wherein the N- alkyl groups containfrom one to four carbon atoms;

1. A process for the manufacture of a 1,1'' lower alkyl or carbamidolower alkyl-disubstituted -4,4''-bipyridylium salt which comprisestreating at 20*C to 80*C the corresponding1,1''-disubstituted-1,1''-4,4''-tetrahydro-4,4''-bipyridyl with anorganic oxidizing agent which has a redox potential in water morepositive than -1.48 volts as compared with the saturated calomelelectrode and which reacts with a hydride ion removed from the saidtetrahydrobipyridyl to form a stable anion which under the conditions ofthe reaction has a redox potential more positive than -0.45 volt ascompared with the saturated calomel electrode, said oxidizing agentbeing selected from the group consisting essentially of alloxan, alloxanmonohydrate, riboflavin, p-quinone dioxime, benzal barbituric acid,isatin, indane trione, methyl red, methyl violet,N-benzyl-3-carbamido-pyridinium chloride, malachite green, methyleneblue, triphenyl-2,4,6,-pyrylium chloroferrate, N-methyl maleimide,phthalimide, phenolphthalein, M-methyl phenazonium methosulphate,2,6-diphenyl pyrylium chloroferrate, N-benzyl nicotinamide chloride,m-dinitrobenzene and beta-nitrostyrene, the said oxidizing agent andbipyridyl being dissolved in an inert organic solvent therefor.
 2. Aprocess as claimed in claim 1 wherein the temperature is less than100*C.
 3. A process as claimed in claim 1 wherein thetetrahydrobipyridyl is employed in the form of a solution in which itsconcentration is about 0.5 mole per liter.
 4. A process as claimed inclaim 1 wherein the organic oxidizing agent is employed in the form of asolution in which its concentration is about 0.5 mole per liter.
 5. Aprocess as claimed in claim 1 wherein the molar ratio of the organicoxidizing agent to the tetrahydrobipyridyl is at least 2:1.
 6. A processas claimed in claim 1 wherein the N-substituents of thetetrahydrobipyridyl are lower alkyl groups.
 7. A process as claimed inclaim 1 wherein the alkyl groups contain from one to six carbon atoms.8. A process as claimed in claim 1 wherein the N-substitutents of thetetrahydrobipyridyl are carbamido lower alkyl groups.
 9. A process asclaimed in claim 1 wherein the said carbamidoalkyl groups areN,N-dialkyl carbamidomethyl groups.